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https://www.readbyqxmd.com/read/28619690/metformin-the-aspirin-of-the-21-st-century-its-role-in-gestational-diabetes-prevention-of-preeclampsia-and-cancer-and-the-promotion-of-longevity
#1
REVIEW
Roberto Romero, Offer Erez, Maik Hüttemann, Eli Maymon, Bogdan Panaitescu, Agustin Conde-Agudelo, Percy Pacora, Bo Hyun Yoon, Lawrence I Grossman
Metformin is everywhere. Originally introduced in clinical practice as an anti-diabetic agent, its role as a therapeutic agent is expanding to include treatment of pre-diabetes, gestational diabetes, polycystic ovarian disease, and more recently, experimental studies, as well as observations in randomized clinical trials, suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes, reviews the results of meta-analyses of metformin in gestational diabetes, and the treatment of obese non-diabetic pregnant women to prevent macrosomia...
June 12, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/28616837/a-phase-ib-study-of-everolimus-combined-with-metformin-for-patients-with-advanced-cancer
#2
Remco J Molenaar, Tim van de Venne, Mariëtte J Weterman, Ron A Mathot, Heinz-Josef Klümpen, Dick J Richel, Johanna W Wilmink
Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78)...
June 15, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28581641/clk1-regulated-aerobic-glycolysis-is-involved-in-gliomas-chemoresistance
#3
Li Zhang, Huicui Yang, Wenbin Zhang, Zhongqin Liang, Qiang Huang, Guoqiang Xu, Xuechu Zhen, Long Tai Zheng
Chemoresistance remains a major challenge for the treatment of glioma. In the present study, we investigated the role of Clk1, which encodes an enzyme that is necessary for ubiquinone biosynthesis in glioma chemoresistance in vitro. The results showed that Clk1 was highly expressed in GL261 mouse glioma cells which were most sensitive to BCNU while was expressed in BCNU resistant cells such as glioma cancer stem cells: T98G, U87MG and U251 glioma cells at low levels. Knockdown of Clk1 in GL261 glioma cells significantly reduced BCNU- or cisplatin- induced cell apoptosis whereas the proliferative activity and the expression of multi-drug resistance -related genes including MDR1, MGMT and GSTP1 were not changed...
June 5, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28580793/rationale-and-protocol-of-metnet-2-trial-lanreotide-autogel-plus-metformin-in-advanced-gastrointestinal-or-lung-neuroendocrine-tumors
#4
Sara Pusceddu, Natalie Prinzi, Giuseppe Lo Russo, Daniela Femia, Massimo Milione, Federica Perrone, Elena Tamborini, Laura Concas, Iolanda Pulice, Claudio Vernieri, Francesca Corti, Roberto Buzzoni, Filippo de Braud
Metformin (MET) has recently emerged as a potentially active agent in cancer prevention and treatment. MET is thought to exert its antitumor effects either via modification of systemic metabolism or through cell-autonomous effects (e.g., activation of AMPK and inhibition of the mTOR pathway). Preliminary findings of the PRIME-NET study suggest that the addition of MET to treatment with everolimus (EVE) and/or somatostatin analogs (SSAs) can provide clinical benefit in diabetic neuroendocrine tumor (NET) patients...
June 5, 2017: Future Oncology
https://www.readbyqxmd.com/read/28571536/amp-activated-protein-kinase-as-a-drug-target-in-chronic-kidney-disease
#5
Soumaya Allouch, Shankar Munusamy
Chronic kidney disease (CKD) is a condition increasingly affecting millions of individuals worldwide and is ranked as the ninth leading cause of death in the United States. AMP-activated protein kinase (AMPK) is an energy sensor that plays a pivotal role in cellular homoeostasis. Deficiency in AMPK activity and autophagic signaling, and sustained activation of mammalian target of rapamycin (mTOR) and endoplasmic reticulum (ER) stress have been shown to promote epithelial-to-mesenchymal transition (EMT) and renal cell apoptosis and contribute to CKD...
June 1, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28548953/from-rapalogs-to-anti-aging-formula
#6
Mikhail V Blagosklonny
Inhibitors of mTOR, including clinically available rapalogs such as rapamycin (Sirolimus) and Everolimus, are gerosuppressants, which suppress cellular senescence. Rapamycin slows aging and extends life span in a variety of species from worm to mammals. Rapalogs can prevent age-related diseases, including cancer, atherosclerosis, obesity, neurodegeneration and retinopathy and potentially rejuvenate stem cells, immunity and metabolism. Here, I further suggest how rapamycin can be combined with metformin, inhibitors of angiotensin II signaling (Losartan, Lisinopril), statins (simvastatin, atorvastatin), propranolol, aspirin and a PDE5 inhibitor...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28533436/metformin-synergizes-with-bcl-xl-bcl-2-inhibitor-abt-263-to-induce-apoptosis-specifically-in-p53-defective-cancer-cells
#7
Xinzhe Li, Bo Li, Zhenhong Ni, Peng Zhou, Bin Wang, Jintao He, Haojun Xiong, Fan Yang, Yaran Wu, Xilin Lyu, Yan Zhang, Yijun Zeng, Jiqin Lian, Fengtian He
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28529619/effects-of-prolonged-exposure-to-low-dose-metformin-in-thyroid-cancer-cell-lines
#8
Safar Kheder, Karen Sisley, Sirwan Hadad, Sabapathy P Balasubramanian
Background: Thyroid cancer is generally associated with an excellent prognosis, but there is significant long-term morbidity with standard treatment. Some sub-types however have a poor prognosis. Metformin, an oral anti-diabetic drug is shown to have anti-cancer effects in several types of cancer (breast, lung and ovarian cancer). The proposed mechanisms include activation of the Adenosine Mono-phosphate-activated Protein Kinase (AMPK) pathway and inhibition of the mTOR pathway (which promotes growth and proliferation)...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28525374/the-effect-of-rapamycin-nvp-bez235-aspirin-and-metformin-on-pi3k-akt-mtor-signaling-pathway-of-pik3ca-related-overgrowth-spectrum-pros
#9
Yasuyo Suzuki, Yasushi Enokido, Kenichiro Yamada, Mie Inaba, Kumiko Kuwata, Naoki Hanada, Tsuyoshi Morishita, Seiji Mizuno, Nobuaki Wakamatsu
The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is critical for cellular growth and metabolism. Recently, mosaic or segmental overgrowth, a clinical condition caused by heterozygous somatic activating mutations in PIK3CA, was established as PIK3CA-related overgrowth spectrum (PROS). In this study, we report a Japanese female diagnosed with PROS, who presented with hyperplasia of the lower extremities, macrodactyly, multiple lipomatosis, and sparse hair. Sequencing and mutant allele frequency analysis of PIK3CA from affected tissues revealed that the patient had a heterozygous mosaic mutation (c...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512260/targeting-metabolism-and-amp-activated-kinase-with-metformin-to-sensitize-non-small-cell-lung-cancer-nsclc-to-cytotoxic-therapy-translational-biology-and-rationale-for-current-clinical-trials
#10
REVIEW
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512156/effects-of-metformin-on-compensatory-pancreatic-%C3%AE-cell-hyperplasia-in-mice-fed-a-high-fat-diet
#11
Kazuki Tajima, Jun Shirakawa, Tomoko Okuyama, Mayu Kyohara, Shunsuke Yamazaki, Yu Togashi, Yasuo Terauchi
Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic β-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication. An 8-week treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 weeks of HFD-feeding was similar in mice treated with and those treated without metformin...
May 16, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28504725/metformin-ameliorates-core-deficits-in-a-mouse-model-of-fragile-x-syndrome
#12
Ilse Gantois, Arkady Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Erika Freemantle, Ruifeng Cao, Vijendra Sharma, Tine Pooters, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong, Shane Wiebe, Isabelle A Groves, Seyed Mehdi Jafarnejad, Clément Chapat, Elizabeth A McCullagh, Karine Gamache, Karim Nader, Jean-Claude Lacaille, Christos G Gkogkas, Nahum Sonenberg
Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1(-/y) mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.
June 2017: Nature Medicine
https://www.readbyqxmd.com/read/28502303/-effect-of-metformin-on-proliferation-and-apoptosis-of-rat-prolactinoma-mmq-cells-and-related-mechanisms
#13
Kai Jin, Lunliang Ruan, Jiujun Pu, Ailing Zhong, Fuchao Wang, Song Tan, Hua Huang, Jiamin Mou, Gang Yang
Objective To investigate the effect of metformin on the cell proliferation, cell cycle and apoptosis of rat prolactinoma MMQ cells in vitro and related molecular mechanisms. Methods The MMQ cells were treated with 1.25, 2.5, 5, 10, 20 mmol/L metformin for 48 hours. CCK-8 assay was used to assess the cell proliferation ability; flow cytometry was used to analyze the cell cycle distribution and apoptosis; Western blotting was performed to detect the expressions of AMPKα1/2, p-AMPKα, mTOR, p-mTOR, insulin like growth factor 1 receptor (IGF-1R), ERK1/2, p-ERK1/2, AKT, p-AKT, P21, CDK4, cyclin D1, caspase-3, cleaved caspase-3(c-caspase-3), Bcl-2 and BAX...
May 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28498475/targeting-hexokinase-2-inhibition-promotes-radiosensitization-in-hpv16%C3%A2-e7-induced-cervical-cancer-and-suppresses-tumor-growth
#14
Yuan Liu, Tracy Murray-Stewart, Robert A Casero, Ioannis Kagiampakis, Lihua Jin, Jiawen Zhang, Huihui Wang, Qi Che, Huan Tong, Jieqi Ke, Feizhou Jiang, Fangyuan Wang, Xiaoping Wan
In order to improve the sensitivity of cervical cancer cells to irradiation therapy, we targeted hexokinase 2 (HK2), the first rate-limiting enzyme of glycolysis, and explore its role in cervical cancer cells. We suppressed HK2 expression and/or function by shRNA and/or metformin and found HK2 inhibition enhanced cells apoptosis with accelerating expression of cleaved PARP and caspase-3. HK2 inhibition also induced much inferior proliferation of cervical cancer cells both in vitro and in vivo with diminishing expression of mTOR, MIB and MGMT...
June 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28464864/metformin-produces-growth-inhibitory-effects-in-combination-with-nutlin-3a-on-malignant-mesothelioma-through-a-cross-talk-between-mtor-and-p53-pathways
#15
Kengo Shimazu, Yuji Tada, Takao Morinaga, Masato Shingyoji, Ikuo Sekine, Hideaki Shimada, Kenzo Hiroshima, Takao Namiki, Koichiro Tatsumi, Masatoshi Tagawa
BACKGROUND: Mesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma. METHODS: We examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses...
May 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28393693/update-on-the-protective-renal-effects-of-metformin-in-diabetic-nephropathy
#16
Andreas Eisenreich, Ulrike Leppert
BACKGROUND: Diabetic nephropathy is one of the most important complications in patients with diabetes mellitus. Main steps crucial for the pathogenesis of diabetic nephropathy involve amongst others the modulation of cell signaling via AMP-activated kinase (AMPK) and mammalian target of rapamycin (mTOR), reactive oxygen generation, and endoplasmic reticulum stress under diabetic or hyperglycemic conditions. These processes mediate increased loss of renal cells, such as podocytes, which consequentially leads to renal damage and loss of renal functions, such as structural integrity and glomerular filtration in diabetic nephropathy...
April 4, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28356082/anti-tumor-effects-of-everolimus-and-metformin-are-complementary-and-glucose-dependent-in-breast-cancer-cells
#17
Gerke Ariaans, Mathilde Jalving, Emma Geertruida Elisabeth de Vries, Steven de Jong
BACKGROUND: Clinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We investigated the glucose-dependent growth-inhibitory properties of everolimus, metformin and the combination in breast cancer cell lines. METHODS: The breast cancer cell lines MCF-7, MDA-MB-231 and T47D were cultured in media containing 11 mM or 2...
March 29, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28339020/metformin-inhibits-endothelial-progenitor-cell-migration-by-decreasing-matrix-metalloproteinases-mmp-2-and-mmp-9-via-the-ampk-mtor-autophagy-pathway
#18
Wen-Dong Li, Neng-Ping Li, Dan-Dan Song, Jian-Jie Rong, Ai-Min Qian, Xiao-Qiang Li
The aim of the present study was to investigate the effect of metformin on endothelial progenitor cell (EPC) migration and to explore the possible mechanisms. EPCs were treated with metformin, and the migration of EPCs was evaluated by wound healing and Matrigel invasion assays. We also examined the expression levels of of MMP-2 and MMP-9 in EPCs with or without metformin treatment via RT-PCR and western blot analysis, and activities of MMP-2 and MMP-9 in EPCs under different conditions was examined by zymography...
March 21, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28338172/antidiabetic-drug-metformin-mitigates-ovarian-cancer-skov3-cell-growth-by-triggering-g2-m-cell-cycle-arrest-and-inhibition-of-m-tor-pi3k-akt-signaling-pathway
#19
Y-L Fu, Q-H Zhang, X-W Wang, H He
OBJECTIVE: Metformin is one of most extensively prescribed oral hypoglycemic drug and has received increased attention in recent times for its antitumorigenic potential. Many possible mechanisms have been proposed for the ability of metformin to overturn cancer growth in vitro and in vivo. The objective of the present study was to evaluate the anticancer activity of metformin against ovarian SKOV3 cancer cells. MATERIALS AND METHODS: Anticancer activity and IC50 value of metformin were determined by MTT assay...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28332630/pml-nuclear-bodies-contribute-to-the-basal-expression-of-the-mtor-inhibitor-ddit4
#20
Jayme Salsman, Alex Stathakis, Ellen Parker, Dudley Chung, Livia E Anthes, Kara L Koskowich, Sara Lahsaee, Daniel Gaston, Kimberly R Kukurba, Kevin S Smith, Ian C Chute, Daniel Léger, Laura D Frost, Stephen B Montgomery, Stephen M Lewis, Christopher Eskiw, Graham Dellaire
The promyelocytic leukemia (PML) protein is an essential component of PML nuclear bodies (PML NBs) frequently lost in cancer. PML NBs coordinate chromosomal regions via modification of nuclear proteins that in turn may regulate genes in the vicinity of these bodies. However, few PML NB-associated genes have been identified. PML and PML NBs can also regulate mTOR and cell fate decisions in response to cellular stresses. We now demonstrate that PML depletion in U2OS cells or TERT-immortalized normal human diploid fibroblasts results in decreased expression of the mTOR inhibitor DDIT4 (REDD1)...
March 23, 2017: Scientific Reports
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